Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy

NCT01871766 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: RMS13NCI-2013-00913
• Study Type: interventional
• Target: 115
• Locations: 1 country
• Sites: 4

Brief Summary

This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy. PRIMARY OBJECTIVE:

• Estimate event-free survival for intermediate risk participants treated with vincristine, dactinomycin and cyclophosphamide with the addition of maintenance anti-angiogenic therapy. SECONDARY OBJECTIVES:
• Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
• Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation.
• Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume.
• Establish the feasibility of delivering 4 cycles of maintenance anti-angiogenic chemotherapy in intermediate and high risk patients following standard chemotherapy.
• Estimate the event free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy.
• Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.

Conditions

Rhabdomyosarcoma

Keywords

Rhabdomyosarcoma; Radiation therapy; Proton beam

Outcome Measures

Primary Outcomes (1)

• Event-free survival (intermediate risk arm)

  To estimate event-free survival for intermediate risk participants treated by vincristine-dactinomycin-cyclophosphamide (VAC) with the addition of maintenance anti-angiogenic therapy

  2 years after last intermediate risk arm enrollment

Secondary Outcomes (10)

• Event-free survival (high risk arm)

  5 years after last high-risk arm enrollment

• Rate of false negative and false positive the sentinel lymph node procedure (low and intermediate risk arms)

  2 years after last low or intermediate arm enrollment

• Rate of false negative and false positive the sentinel lymph node procedure (high risk arm)

  5 years after last high risk arm enrollment

• Local failure rate (low and intermediate risk arms)

  2 years after last low or intermediate risk arm enrollment

• Local failure rate (high risk arm)

  5 years after last high risk arm enrollment

Study Arms (4)

Low-Risk, Subset 1

EXPERIMENTAL

Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin and cyclophosphamide). They are then evaluated to determine how the tumor responded to treatment. Twelve additional weeks of chemotherapy (vincristine and dactinomycin) is given, followed by evaluation for tumor response. No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Drug: Vincristine; Drug: Dactinomycin; Drug: Cyclophosphamide; Procedure: Surgical Resection; Procedure: Radiation; Drug: Myeloid Growth Factor; Procedure: Lymph Node Sampling; Drug: ^1^1C-methionine

Low-Risk, Subset 2

EXPERIMENTAL

Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated to determine how it responded to treatment. Radiation therapy and/or surgical resection is performed to destroy or remove the remaining tumor. Twelve additional weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is given, followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants then receive 16 weeks of additional chemotherapy (vincristine, dactinomycin and cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor will be given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Drug: Vincristine; Drug: Dactinomycin; Drug: Cyclophosphamide; Procedure: Radiation; Drug: Myeloid Growth Factor; Procedure: Lymph Node Sampling; Drug: ^1^1C-methionine

Intermediate-Risk

EXPERIMENTAL

Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated for treatment response. Radiation therapy and/or surgical resection is done. Twelve weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants receive 16 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) followed by 12 weeks of maintenance treatment (bevacizumab, sorafenib, oral cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Drug: Vincristine; Drug: Dactinomycin; Drug: Cyclophosphamide; Procedure: Surgical Resection; Procedure: Radiation; Drug: Bevacizumab; Drug: Sorafenib; Drug: Myeloid Growth Factor; Procedure: Lymph Node Sampling; Drug: ^1^1C-methionine

High-Risk

EXPERIMENTAL

Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 6 weeks (2 cycles) chemotherapy (vincristine and irinotecan). The tumor is evaluated for treatment response. 3 cycles of chemotherapy \[vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide (or etoposide phosphate) (VDC/IE)\] are given. Dexrazoxane is given prior to each dose of doxorubicin. Radiation therapy begins at week 4 or 20 (depending on tumor location) while receiving vincristine and irinotecan. 2 cycles of VDC/IE, 4 cycles of modified vincristine, dactinomycin, cyclophosphamide (VAC), then 2 cycles of modified vincristine/irinotecan (total of 54 weeks). High risk participants also receive additional maintenance therapy beginning week 55 with anti-angiogenic chemotherapy (bevacizumab, sorafenib, cyclophosphamide). Myeloid growth factor is given as needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Drug: Vincristine; Drug: Dactinomycin; Drug: Cyclophosphamide; Procedure: Surgical Resection; Procedure: Radiation; Drug: Bevacizumab; Drug: Sorafenib; Drug: Myeloid Growth Factor; Procedure: Lymph Node Sampling; Drug: Irinotecan; Drug: Ifosfamide; Drug: Etoposide; Drug: Etoposide Phosphate; Drug: Doxorubicin; Drug: Dexrazoxane; Drug: ^1^1C-methionine

Interventions

Dactinomycin DRUG

Dosage and route of administration: * \< 1 year=0.025 mg/kg IV push * ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.

Also known as: Actinomycin-D, Cosmegen®

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Cyclophosphamide DRUG

Dosage and route of administration: During VAC chemotherapy: * \< 3 years of age = 40 mg/kg IV * ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA. During maintenance for intermediate-risk participants: * oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)

Also known as: Cytoxan(R)

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Surgical Resection PROCEDURE

Surgery will be performed for the primary site tumor with the goal of removing tumor cells while maintaining function in the organ or adjacent organs involved.

Also known as: Surgery

High-Risk; Intermediate-Risk; Low-Risk, Subset 1

Vincristine DRUG

Dosage and route of administration: * \< 1 year of age=0.025 mg/kg intravenously (IV) * \> 1 year and \< 3 years= 0.05 mg/kg IV * ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.

Also known as: Oncovin®

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Etoposide Phosphate DRUG

Dosage and Route of Administration: Used in substitution for etoposide in participants who experience allergic reaction. It will be administered 100 mg/m\^2/day IV.

Also known as: Etopophos®

High-Risk

Radiation PROCEDURE

Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.

Also known as: Proton Beam Radiation, External Beam Radiation, Brachytherapy

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Bevacizumab DRUG

Dosage and route of administration: 15 mg/kg/dose/day IV.

Also known as: rhuMab, VEGF, Avastin®

High-Risk; Intermediate-Risk

Sorafenib DRUG

Dosage and route of administration: 90 mg/m\^2/dose twice daily.

Also known as: Nexavar®

High-Risk; Intermediate-Risk

Myeloid Growth Factor DRUG

If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice. High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.

Also known as: G-CSF, Filgrastim, Pegfilgrastim

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Lymph Node Sampling PROCEDURE

Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Irinotecan DRUG

Dosage and Route Administration: During interval compressed therapy - irinotecan 50mg/m\^2 IV (maximum dose 100 mg/day) daily x 5.

Also known as: Camptosar ®

High-Risk

Ifosfamide DRUG

Dosage and Route of Administration: During interval compressed therapy - Age \> 1 year: 1800 mg/m\^2/day IV x 5 Age \<1 year: treat with 50% doses calculated on a m\^2 basis.

Also known as: Ifex ®

High-Risk

Etoposide DRUG

Dosage and Route of Administration: Age \>1 year 100 mg/m\^2/day IV x 5 Age \< 1 year treat with 50% doses calculated on a m\^2 basis

Also known as: VP-16, Vepesid®

High-Risk

Doxorubicin DRUG

Dosage and route of Administration: Age ≥1 year, 37.5 mg/m\^2 IV over 1 hour x 2 days Age \<1 year, 18.75 mg/m\^2 (i.e., a 50% dose reduction) IV over 1 hour x 2 days.

Also known as: Adriamycin®

High-Risk

Dexrazoxane DRUG

Dosage and Route of Administration: Dexrazoxane dose should be 10x that of doxorubicin. Age ≥1 year, 375 mg/m\^2 IV over 15-30 minutes Age \<1 year, 187l.5 mg/m\^2 (i.e., a 50% dose reduction) IV over 15-30 minutes.

Also known as: Zinecard

High-Risk

^1^1C-methionine DRUG

Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.

Also known as: Contrast Media

High-Risk; Intermediate-Risk; Low-Risk, Subset 1; Low-Risk, Subset 2

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Newly diagnosed participants with localized rhabdomyosarcoma (RMS).
• Must have either low-, intermediate-, or high-risk disease, defined as:
• Low-risk: Embryonal, botryoid, spindle cell tumors only (Subset 1: Stage 1, Group I; Stage 1 Group I; Stage 1 Group III orbital only; Stage 2 Group I; Stage 2 Group II) (Subset 2: Stage 1 Group III non orbit; Stage 3 Group I, II)
• Intermediate-risk: Embryonal, botryoid, or spindle cell RMS Stage 2 or 3 and Group III; Alveolar, undifferentiated, or anaplastic RMS: Stage 1-3, group I-I; I)
• High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4).
• Participants treated on this protocol in the low or intermediate risk arm who experience disease progression prior to week 13 will transfer to the high risk arm and proceed with high risk chemotherapy starting at week 1 of the protocol.
• Age \< 22 years (eligible until 22nd birthday)
• Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants \< 16 years
• Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment. Prior biopsy, surgical resection and lymph node sampling is allowed.
• Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection.
• Adequate bone marrow function defined as:
• Peripheral absolute neutrophil count (ANC) ≥ 750/μL
• Platelet count ≥ 75,000/μL (transfusion independent)
• Adequate liver function defined as total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met.
• Adequate renal function defined as:

You may not qualify if:

• Newly diagnosis or suspected diagnosis of previously untreated participants with rhabdomyosarcoma (RMS). NOTE: Patients with suspected diagnosis of RMS may enroll on screening part of study but must have histologic diagnosis to enroll on treatment part of study.
• Must have either intermediate-risk or high risk disease.
• years of age.
• Undergoing upfront surgical resection of the primary tumor.
• History of allergy to Optison(TM) contrast agent or blood products.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (4)

University of Florida Proton Therapy Institute

Jacksonville, Florida, 32206, United States

Location

Nemours Children's Clinic

Jacksonville, Florida, 32207, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Related Publications (1)

• Patel AG, Chen X, Huang X, Clay MR, Komorova N, Krasin MJ, Pappo A, Tillman H, Orr BA, McEvoy J, Gordon B, Blankenship K, Reilly C, Zhou X, Norrie JL, Karlstrom A, Yu J, Wodarz D, Stewart E, Dyer MA. The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma. Dev Cell. 2022 May 23;57(10):1226-1240.e8. doi: 10.1016/j.devcel.2022.04.003. Epub 2022 Apr 27.

  PMID: 35483358 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Rhabdomyosarcoma

Interventions

Vincristine; Dactinomycin; Cyclophosphamide; Surgical Procedures, Operative; Radiation; Proton Therapy; Brachytherapy; Bevacizumab; Vascular Endothelial Growth Factor A; Sorafenib; Granulocyte Colony-Stimulating Factor; Filgrastim; pegfilgrastim; Irinotecan; Ifosfamide; Etoposide; etoposide phosphate; Doxorubicin; Dexrazoxane; Contrast Media

Condition Hierarchy (Ancestors)

Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Heterocyclic Compounds, 3-Ring; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Physical Phenomena; Heavy Ion Radiotherapy; Radiotherapy; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Vascular Endothelial Growth Factors; Angiogenic Proteins; Intercellular Signaling Peptides and Proteins; Biological Factors; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Camptothecin; Oxazines; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Glucosides; Glycosides; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Razoxane; Diketopiperazines; Piperazines; Diagnostic Uses of Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals

Study Officials

• Matthew J. Krasin, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2013
• First Posted: June 7, 2013
• Study Start: December 4, 2013
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2030
• Last Updated: April 24, 2026

Record last verified: 2026-04

Locations

US (4)